Proteomic profiling reveals the prognostic value of adenomatous polyposis coli-end-binding protein 1 in hepatocellular carcinoma.
Histological differentiation is a major pathological parameter associated with poor prognosis in patients with hepatocellular carcinoma (HCC) and the molecular signature underlying HCC differentiation may involve key proteins potentially affecting the malignant characters of HCC. To develop prognostic biomarkers for HCC, we examined the global protein expression profiles of 45 surgically resected tissues, including 27 HCCs with different degree of histological differentiation, 11 adjacent nontumor tissues, and seven normal liver tissues. Unsupervised classification grouped the 45 samples according to their histological classification based on the protein expression profiles created by laser microdissection and two-dimensional difference gel electrophoresis (2D-DIGE). Statistical analysis and mass spectrometry identified 26 proteins with differential expression, of which 14 were functionally linked to c-Myc, AP-1, HIF1A, hepatocyte nuclear factor 4 alpha, or the Ras superfamily (RhoA, CDC42, and Rac1). Among the proteins identified, we focused on APC-binding protein EB1 (EB1) because it was dominantly expressed in poorly differentiated HCCs, which generally correlate with the poor prognosis in patients with HCC. In addition, EB1 is controlled by c-Myc, RhoA, and CDC42, which have all been linked to HCC malignancy. Immunohistochemistry in a further 145 HCC cases revealed that EB1 significantly correlated with the degree of histological differentiation (P < 0.001), and univariate and multivariate analyses indicated that EB1 is an independent prognostic factor for recurrence (hazard ratio, 2.740; 95% confidence interval, 1.771-4.239; P < 0.001) and survival (hazard ratio, 2.256; 95% confidence interval, 1.337-3.807; P = 0.002) of patients with HCC after curative surgery.


CONCLUSIONS
Proteomic profiling revealed the molecular signature behind the progression of HCC, and the prognostic value of EB1 in HCC.
Orimo
Tatsuya
T
Proteome Bioinformatics Project, National Cancer Center Hospital, Tokyo, Japan.
Ojima
Hidenori
H
Hiraoka
Nobuyoshi
N
Saito
Shigeru
S
Kosuge
Tomoo
T
Kakisaka
Tatsuhiko
T
Yokoo
Hideki
H
Nakanishi
Kazuaki
K
Kamiyama
Toshiya
T
Todo
Satoru
S
Hirohashi
Setsuo
S
Kondo
Tadashi
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000453:epidemiology; D011379:Prognosis; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C500985:MAPRE1 protein, human; C489427:MYC protein, human; D008869:Microtubule-Associated Proteins; D016271:Proto-Oncogene Proteins c-myc; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein